Beyond C4d: Other Complement-Related Diagnostic Approaches to Antibody-Mediated Rejection

Complement is a multifunctional system of receptors and regulators as well as effector molecules. Both the pathogenic and diagnostic power of complement is based on the capacity of the complement system to amplify innate and adaptive immunity. This amplification is accomplished through two strategies: (1) enzymatic reactions in the complement cascade, and (2) stimulation of leukocytes, platelets and parenchymal cells through specific receptors or receptor-independent pore formation. The mechanisms by which complement mediates and modifies nonspecific inflammation, antibody-mediated injury and T-cell responses are of particular significance to the pathogenesis of transplant rejection. Understanding the mechanisms by which complement integrates the interactions of leukocytes, platelets and parenchymal cells offers opportunities to further refine the diagnosis of rejection.     

The effect of concomitant disorders in childhood depression on predicting treatment response

Children with pure depression or depression plus an anxiety-related disorder (n = 14) had a higher drug response rate (57%) and a lower placebo response rate (20%) when compared to children with depression plus a concomitant conduct or oppositional disorder (n = 17) (33% drug response rate and 67% placebo response rate). These findings could explain why studies of prepubertal-onset depression found no differences between drug and placebo treatment assuming that a large percentage of the studies' subjects had concomitant conduct or oppositional disorders. The children with pure depression or depression plus an anxiety-related disorder had different symptom clusters from those with depression plus a concomitant conduct or oppositional disorder. The former had more severe CDRS ratings on sleep, appetite disturbance, depressed feelings, and psychomotor retardation. In contrast, those with a concomitant conduct or oppositional disorder had shorter attention spans and were more likely to disturb other children (based on Conners scale scores).     

The Effect of Flurbiprofen on Steady-State Plasma Lithium Levels

Study Objective . To evaluate the effects of flurbiprofen therapy on the pharmacokinetics of lithium. Design . Placebo-controlled, single-blind, crossover study. Setting . University-affiliated hospital. Patients . Eleven healthy women with bipolar disorder. Interventions . The subjects received therapeutic doses of lithium administered as an immediate-release capsule every 12 hours. In addition, they received one placebo tablet every 12 hours during phase I and flurbiprofen 100 mg every 12 hours during phase II of the study. Measurements and Main Results . Steady-state pharmacokinetic parameters were measured for each phase. Lithium trough plasma concentration (C_min) and area under the curve were statistically significantly increased (p<0.05) when patients received flurbiprofen. Flurbiprofen also caused decreases in lithium clearance and 24-hour lithium urine excretion, although the changes did not reach statistical significance. Clinically significant increases in C_min appeared to be associated with a greater than 1000-μg/24 hour decrease in urinary excretion of prostaglandin E₂. Conclusion . Patients with clinically normal renal function may experience an increase in lithium levels with the initiation of flurbiprofen therapy.     

Chondrocyte-seeded hydroxyapatite for repair of large articular cartilage defects. A pilot study in the goat

The aim of this study was to evaluate the potential for restoration of a large cartilage defect in the goat knee with hydroxyapatite (HA) loaded with chondrocytes. Isolated chondrocytes were suspended in fibrin glue, seeded on top of the HA, and then the composite graft was implanted in the defect. After transplantation, cell behaviour, newly synthesised matrix and the HA–glue interface were assessed histologically after 2, 4, 12, 26 and 52 weeks. Special attention was paid to the incorporation process of HA in the subchondral bone and interactions between this biomaterial and the fibrin-glue–chondrocyte suspension.

Chondrocytes in the glue proved to survive the transplantation procedure and produced new metachromatically stained matrix two weeks after implantation. The glue–cell suspension had penetrated the superficial porous structure of the HA. Four weeks after surgery, islands of hyaline-like cartilage were observed at the HA–glue interface. A layer of fibrous tissue was formed surrounding the HA graft, resulting in a relatively instable fixation of the HA in the defect. This instability of the graft in the defect, possibly together with early weight bearing, resulted in a gradual loss of the newly formed hyaline cartilage-like repair tissue. Progressive resorption of the HA occurred without any sign of active bone remodelling from the host site. One year after surgery part of the defect which extended down to the cancellous bone had been predominantly restored with newly formed lamellar bone. Only small HA remnants were still present at the bottom of the original defect. Resurfacing of the joint had occurred with fibrocartilaginous repair tissue.

The absence of adequate fixation capacity of the HA near the joint space resulted in a relative instability of the graft with progressive resorption. Therefore, HA is not a suitable biomaterial to facilitate the repair of large articular cartilage defects.     

The management of patients with an intrinsic supratentorial brain tumour

The management of patients presenting with supratentorial glioma between 1978 and 1986 is reviewed. Complete follow-up in 517 cases was obtained. One hundred and fifty eight patients were not submitted to any form of surgery, 299 patients were biopsied and 60 patients underwent craniotomy and internal decompression. The no surgery group contained a higher proportion of patients with poor prognostic indicators than either the biopsy or craniotomy groups. The craniotomy group consisted of patients with better prognostic indicators than the biopsy group, in particular, younger age and more favourable site, type and grade of tumour. This was reflected in the difference in outcome between the groups. Median survival was 14 months in the craniotomy group, four months in the biopsy group and 2.2 months in the no surgery group. The outcome in patients with histologically proven malignant gliomas was best in those patients who received radiotherapy. The craniotomy group had a median survival of 18.5 months, a two year survival of 48% and a five year survival of 9%. The median survival following radiotherapy of those patients with proven malignant gliomas who had a biopsy was 9.5 months with a two year survival of 16% and a five year survival of 2%. These results compare favourably with studies which have adopted a more aggressive approach, suggesting that outcome is determined as much by patient selection using favourable prognostic indicators as by the treatment itself. The need for prospective trials of the management of unselected consecutive glioma patients randomizing them to conservative and radical treatment groups in order to define the role of both conventional therapy and radical therapy is discussed.     

Chronic cyclosporine nephrotoxicity in renal transplantation

Although extensively studied, the pathophysiologic characteristics of chronic cyclosporine (CsA) nephrotoxicity are still far from being completely understood. The recognition of chronic CsA nephrotoxicity in allografted kidneys is hampered by a lack of easily assessable sensitive and specific markers. Long-term results of CsA withdrawal trials and trials that evaluated CsA sparing or withdrawal after the diagnosis of chronic allograft nephropathy (CAN) have shown that chronic CsA nephrotoxicity has a more important role in the etiology of late transplant dysfunction than appreciated before. Various hypotheses have explained the renal structural changes of chronic CsA nephrotoxicity including ischemia, cellular toxicity, and the stimulation of renal fibrosis by growth factors or cytokines. Possible ways to prevent chronic CsA nephrotoxicity include improved therapeutic drug monitoring and CsA withdrawal or avoidance. Patients with aspecific CAN in late biopsy may benefit from withdrawal of CsA or a reduction of its dose. Current knowledge is being discussed. It is concluded that in the near future more strategies are likely to be used to prevent loss of allograft function as a result of drug toxicity.